AMG487 inhibits PRRSV replication and ameliorates lung injury in pig lung xenografts by down-regulating the expression of ANXA2

Porcine reproductive and respiratory syndrome (PRRS) is a pig disease caused by the PRRS virus (PRRSV) that is characterized with diffuse interstitial pneumonia and lung edema. High expressions of chemokine CXCL10 and its receptor CXCR3 are reported in infected porcine lungs. Since CXCR3 is a key player in host inflammatory response, it might be a therapeutic target to treat lung damage caused by PRRSV infection. The size of pigs has long hampered research into molecular mechanisms of PRRS and validating the potential pharmaceutical targets. In this study, a porcine lung xenograft model with PRRSV infection was generated in immunodeficient mice to evaluate the therapeutic effects of the CXCR3 antagonist AMG487 on PRRSV infection-induced lung injury. The porcine lung tissues developed normally two weeks after xeno-transplantation in the mouse kidney capsule. Infection of PRRSV resulted in its efficient replication in the xenografts and histological damage to the porcine lung tissue structure, with no or little effects on mouse lungs. AMG487 administration dramatically reduced the number of PRRSV genome copies and significantly alleviated the porcine lung injury. Furthermore, treatment of AMG487 in cultured porcine macrophages consistently suppressed PRRSV replication with significant downregulation of Annexin A2 (ANXA2), a cellular protein facilitating viral replication. These findings provide a suitable model for evaluating new antiviral therapies as well as a possible therapeutic option for virus infection-induced lung injury.